CN100469394C - Implants with FK506 - Google Patents

Abstract

The present invention relates to an implant, in particular an intraluminal or intravascular implant, preferably for the treatment or prevention of coronary or peripheral vascular constriction or occlusion, in particular constriction or stenosis or restenosis, preferably for the prevention of restenosis , which comprises FK506 in the form of chemical covalent binding, non-covalent binding or physical immobilization, and the present invention also relates to methods for producing and using the implant.

Description

Implants with FK506

technical field

The present invention relates to implants, in particular intraluminal or intravascular implants, preferably for the treatment or prevention of coronary or peripheral vascular occlusion, or vascular narrowing, in particular narrowing and stenosis or restenosis, preferably for the prophylaxis Restenosis. It includes chemically covalently or non-covalently bound or physically immobilized FK596, and the invention also relates to methods for producing and using it.

Background technique

The formation of atherosclerotic lesions in arterial vessels is a broad spectrum of clinical symptoms, ranging from angina pectoris to intermittent claudication to myocardial infarction and ischemic stroke, all of which are based on atheromer formation and/or or narrow lesions. The term stenotic lesion refers to a local reduction of the lumen of a vessel to less than 60-70% of its normal diameter. This in turn leads to a significant decrease in the supply of oxygen and nutrients to specific tissues. Although drug therapy (statins, ACE inhibitors, gpIIa/IIIb blockers, and plasminogen activators) has shown promising therapeutic outcomes in the last decade, especially in the field of cardiovascular disease, the Surgical intervention (bypass surgery, etc.) is still required for patients who have developed a complete ischemic state. These procedures are quite complex and expensive and involve the risk of serious complications.

To prevent the development of ischemic heart disease, minimally invasive surgical methods have been developed. The development of percutaneous transluminal coronary angioplasty (PTCA) in the late 1970s was a major breakthrough in the field of cardiology. PTCA involves the use of an inflatable balloon that can be advanced as far as the coronary artery stenosis lesion. These balloons are then inflated at specific target locations to dilate the narrowed area. Similar procedures are also used for dilation of the carotid or peripheral arteries.

Nevertheless, relapse of stenosis at sites dilated with balloon catheters was observed in a substantial proportion of PTCA patients after a relatively short time. In this respect, it was found that the cause of this so-called restenosis is due to the remodeling of the vascular structure of the tissue layers. The introduction of tubular vascular metal implants known as stents has ameliorated the situation in transluminal treatment of stenosis. Clinical studies have shown (Serruys et al., N. Engl. J. Med. 331 (1994) 489-495) that the use of a stent at the site of balloon inflation can reduce the incidence of restenosis by approximately 45% to 30%. Although this is considered to be a significant improvement in preventing the sequelae of restenosis, it is still a significant stimulus for improvement in treatment.

In a detailed study of the pathophysiology of restenosis, it has been found that restenosis in stents differs from PTCA-induced restenosis. Inflammation, hyperproliferation, and migration of smooth muscle cells (SMCs) are important factors in neointima formation leading to restenosis in stents. In animal models of restenosis, and even in human tissues, hyperproliferation of smooth muscle cells has been found to be associated with infiltration of macrophages and T cells into the tissue surrounding the area of stent reinforcement (Grewe et al., J. Am. Coll. Cardiol. 35 (2000) 157-63). Similar to other clinical indications involving inflammatory responses and hyperproliferation of cells, and which can be controlled with medical treatment, attempts have been made to treat restenosis with drugs. The selected active agent has been administered orally or intravenously or delivered to the site of action by a perforated catheter. Unfortunately, so far no active agent has been able to significantly reduce restenosis (Gruberg et al., Exp. Opin. Inyest. Active agents 9 (2000) 2555-2578).

Direct delivery of pharmaceutically active agents from active agent-coated stents is the method of choice here. Preliminary results from animal experiments and clinical trials with active agent-coated stents gave the impression that delayed release of immunosuppressive or antiproliferative active agents reduces the risk of restenosis. Panitesi, a cytostatic agent, and the immunosuppressant and cytostatic agent rapamycin, have been tested in animals. Both compounds were able to inhibit neointima formation (Herdeg et al., Semin Intervent Cardiol 3 (1998) 197-199; Hunter et al., Adv. Active agent. Delivery Rev. 26 (1997) 199-207; Burke et al., J. Cardiovasc Pharmacol. 33 (1999) 829=835; Gallo et al., Circulation 99 (1999) 2164-2170). Loss of effect was observed 6 months after implantation of Panitesi-coated stents in pigs (Heldman, International Local Active agent Delivery Meeting and Cardiovascular Course on Radiation, Geneva, Jan 25-27, 2001). In initial clinical use, rapamycin showed a good effect of complete resolution of restenosis (Sousa et al., Circulation 103 (2001) 192-195). On the other hand, this appears to be consistent with delayed healing of vessel wall injuries in balloon angioplasty and stent implantation.

Overall, the balance between arterial wall healing and controlled neointima formation after angioplasty and stent placement is very important. To achieve this balance, active agents that selectively interfere with the specific mechanisms leading to neointima formation should be used.

Contents of the invention

It is therefore an object of the present invention to provide an implant having advantageous properties for the treatment and prevention of restenosis.

Accordingly, the present invention relates to an implant comprising FK506 in chemically covalently bound or non-covalently bound or physically immobilized form, and optionally at least one other active agent.

In this regard, the following description applies to each active agent mentioned above for the purposes of the present invention, including the active agent FK506: The term "active agent" also includes direct derivatives of the active agent, and the active agent can also be used in any Types of salts, enantiomers, racemates, bases or free acids of active agents, and mixtures thereof.

Preferably the implant is an intraluminal implant, preferably an intravascular implant.

Here, intraluminal means within a cavity, especially within a hollow organ or organs such as a blood vessel, esophagus, ureter, bile duct or the like.

Intravascular, specifically, means application within a blood vessel.

It is also preferred that the implant is suitable for the treatment or prevention of narrowing or occlusion of coronary or peripheral vessels, in particular narrowing or stenosis or restenosis, preferably for the prevention of restenosis.

Therefore, particularly preferred are intraluminal, preferably intravascular, implants for the treatment or prevention of coronary or peripheral vascular constriction or occlusion, in particular constriction or stenosis or restenosis, preferably for the prevention of restenosis, which The implant comprises FK506 in chemically covalently bound or non-covalently bound or physically immobilized form, and optionally at least one other active agent.

Macrolide antibiotic FK506 (tacrolimus, [3S-[3R*[E(1S*, 3S*, 4S*)], 4S*, 5R*, -8S*, 9E, 12R*, 14R*, 15S*, 16R*, 18S*, 19S*, 26aR*]]-5, 6, 8, 11, 12, 13, 14, 15, 16, 17, 18, 19, 24, 25, 25, 26, 26a -Hexadecahydro-5,19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylvinyl]-14,16-dimethoxy-4, 10,12,18-Tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido-[2,1-c][1,4]oxazepine-cyclobis Tridecane (cyclotricosine)-1,7-20,21(4H,23H)-tetraketone; Merck Index No. 9000) is an active agent developed for use as a transplant medicine. FK506 inhibits the release of interleukin-2 (IL-2) and interferon-γ (IFN-γ) from T cells, thus blocking the rejection of implants (grafts) (Wiederrecht et al., Ann.NY Acad. Sci. 696 (1993) 9-19). The effect of FK506 on smooth muscle cell proliferation inhibition in smooth muscle cell culture was also studied (Mohacsi et al., J.Heart Lung Transplant.16(1997)484-492; Marx et al., Circulation Res.76(1995)412-417) and inhibition of smooth muscle Cell migration (Poon et al., J. Clin. Invest. 98 (1996) 2777-2283). In general, many investigators have evaluated FK506 as inappropriate because of its low activity in preventing restenosis (Mohasci et al., (1997); Poon et al. (1996); Marx et al. 1995; Dell, Curr Med Chem 5 (1998) 179-94) . Mohacsi et al. found half-maximal inhibition of smooth muscle proliferation between 100 nM and 1 μM, while Marx et al. observed no effect at all at concentrations as high as 123 nM. In contrast, rapamycin was active in inhibiting the proliferation of cultured smooth muscle cells in the nanomolar concentration range.

According to these prior art, it would not at all conceivable to use FK506 specifically to inhibit restenosis (Mohacsi et al. (1997); Poon et al. (1996). Stents, which can of course be part of other implants, are effective in the treatment and prevention of restenosis. In particular, local administration of FK506 is beneficial in the prevention of restenosis, which is very well balanced because it also The wall endothelium re-healed well.

Rather than assuming this at the outset, this may be explained by the immunomodulatory activity of FK506, which can be inhibited half-maximally by IL-2 release at a concentration of about 0.1 nM (Kimo et al., J.Antibiot.40 (1987) 1256- 1265) and inhibition of smooth muscle cell proliferation at approximately 300-500 nM. Therefore, it is advantageous to use FK506.

Herein, stenosis means occlusion or narrowing of blood vessels, and restenosis means recurrence of stenosis.

In addition, in this context, "comprising" also means, in particular, eg non-covalently bound coatings.

In addition, herein, "peripheral" means blood vessels or other hollow organs other than the heart and coronary vessels.

Binding by "chemically non-covalent" means inter alia linkage via interactions such as hydrogen bonds, hydrophobic interactions, van der Waals forces, and the like.

Physical immobilization means, for example, membrane encapsulation in holes, or spatial trapping through selected apertures.

An implant is any type of man-made object that is introduced into the body (even for a limited time). They may be eg intraluminal, intravascular implants. Examples are stents, grafts, stent grafts, graft connectors, guidewires, catheter pumps or catheters.

A stent for the purposes of the present invention refers to an elongated implant having a hollow interior and at least two orifices, usually with a circular or oval cross-section, but may be of any other shape ( Mostly made of metal, but optionally also plastic materials or polymers), preferably with a perforated, lattice-like structure, which is implanted in the lumen, especially a blood vessel, to keep it open and functional .

Graft for the purposes of the present invention means an elongated implant having a hollow interior and at least two orifices, usually of circular or oval, but also any other shape, cross-section, and having at least one Closed polymeric surface, which is homogeneous, or optionally woven from various strands, impermeable to corpuscular constituents of blood and/or water, such implants are generally used as Vascular prostheses are often used to replace damaged blood vessels or to replace blood vessels.

A stent graft for the purposes of the present invention refers to the connection between the stent and the graft. Thus, a stent graft is essentially a vascular prosthesis reinforced by a stent (see grafts described above) in which the polymer layer is homogeneous or optionally composed of various The thin bands are woven and impermeable to the particulate components of blood and/or water. In the narrow sense, this is a stent having, on at least 20% of the implant surface, a perforated (lattice-like), preferably metallic, outer layer and at least one inner or outer layer located on the outer layer. An outer, closed polymeric layer that is homogeneous or optionally woven from various thin strips, impermeable to the particulate components of blood and/or water, and optionally (when the perforated layer is located on the outer Bottom) An additional perforated (lattice-like), preferably metallic, inner layer inside the polymer layer, or external, outside the perforated layer, homogeneous or optionally composed of various fine A closed polymer layer that is woven and impermeable to the particulate components of blood and/or water.

Graft connector for the purposes of the present invention means an implant connecting at least two hollow organs, vessels or grafts, which consists of materials used in grafts or stent grafts And/or have the latter structure, and correspondingly have at least two, preferably three or four openings, especially in an asymmetrical "T" shape.

A catheter for the purposes of the present invention refers to a tubular instrument for introduction into a hollow organ. In the narrow sense, they are preferably guide, angioplasty or balloon catheters.

A catheter pump for the purposes of the present invention refers to a catheter in which a pusher that assists the pumping of the myocardium is disposed at the tip of the catheter.

Another preferred embodiment of the implant according to the invention is that the implant has at least one closed or perforated layer or surface, the latter consisting of metal or metal alloy, homogeneous or braided by various thin strips made.

A metal or a metal alloy for the purposes of the present invention refers in particular to steel or a steel alloy or to nickel or a nickel alloy, the term metal from the beginning also including metal alloys.

A perforated structure means especially a lattice-like or woven or braided structure.

Another preferred embodiment of the implant according to the invention is that the implant has at least one closed or perforated layer or surface, the latter consisting of a polymer, homogeneous or braided from various thin strips.

In a preferred embodiment, the implant has at least one polymer layer which completely or partially covers a homogeneous or closed or porous layer formed of metal or alloy or formed of various thin strips or The surface, the latter preferably having an optionally lattice-like structure composed of a metal or alloy.

In a particularly preferred embodiment, the implant has at least one closed or perforated layer or surface, which consists of metal or a metal alloy and is homogeneous or formed of various thin bands, and at least one closed or perforated layer or surface made of polymer and homogeneous or formed of various thin bands.

It is very particularly preferred for the implant that the layer or surface made of metal or metal alloy is an optionally lattice-like structure made of metal or metal alloy and/or the layer or surface made of polymer is Homogeneously closed or woven, and/or impermeable to water and/or corpuscle, and/or the order of layers and surfaces will be metal-polymer, polymer-metal, metal-polymer from outside to inside - a metal or polymer-metal-polymer, and/or a layer or surface composed of a polymer will be non-chemically (covalently or non-covalently) bonded to a layer or surface composed of a metal or metal alloy, Or a layer or surface composed of a polymer will be attached to a layer or surface composed of a metal or metal alloy by an adhesive.

It is further preferred that the polymer used for the implant is selected from Dacron, PTFE/Teflon (foamable or non-foamable), or polyurethane. It is preferably selected from polytetrafluoroethylene (PTFE) (expandable or non-expandable) or polyurethane, more preferably PTFE.

In a preferred embodiment of the invention the implant is a stent, a stent graft, a graft, a graft connector, a guide wire, a catheter or a catheter pump, preferably a stent, A stent graft, graft or graft connector, more preferably a stent or a stent graft.

A particularly preferred implant of the invention is an implant coated with FK506.

Local delivery of FK506 can be achieved by direct delivery from the active agent-loaded surface of a coronary or peripheral vascular stent. The active agent loaded surface of the stent can be obtained by using various technical methods. Each method can be performed in such a way that the active agent is released from the surface for a short period (hours) or for an extended period (days). Release kinetics can be tuned by specific modifications to the surface, such as hydrophobic or hydrophilic side chains on polymeric supports or ceramic surfaces. These surfaces can also be modified on the surface, for example by Si groups on the aluminum oxide layer.

The release kinetics can be adjusted by using specific polymers, block polymers, polymer mixtures, grafted polymers alone or in layered structures. The release kinetics can be particularly suitably controlled by using nanocapsules and/or liposomes in combination with the aforementioned polymers. Nanocapsules generally refer to micellar systems or coatings of colloidal solids to obtain very fine particles coated with solids. Coated particles whose size is in the nanometer range form a colloidal solution. Thus, nanoencapsulated active agents with prolonged activity may be used. Liposomes are generally formed by dispersing phospholipids in an aqueous medium, which is of interest here because hydrophilic active agents can be incorporated into the aqueous interior volume and into the aqueous middle layer, while hydrophobic active agents can enter to the lipid layer. If nanocapsules and/or liposomes of different composition are used, the latter can be loaded with different active agents so that combinations of active agents can be released in a targeted manner.

ceramic coating

Amounts of 10 micrograms to 10 milligrams of FK506 can be loaded onto alumina coatings with porous surfaces by dipping, spraying or similar techniques (patent applications DE19855421, DE19910188, WO 00/25841). The dosage of the active agent depends on the type of target vessel and the condition of the patient, and can be selected so as to sufficiently inhibit proliferation, migration and T cell responses without affecting the healing process. FK506 can be used in aqueous or organic solutions such as DMSO, DMF and ethanol. After spraying or dipping (optionally under mild vacuum), the treated stent is dried and the procedure is repeated 2-10 times. Another application possibility is the direct transfer of the active agent solution onto the strands of the stent by means of a micropipette or automatic pipette. After the final drying step, the stent can be rinsed with water or isotonic saline for 1 min at room temperature before drying. After the active agent has been dissolved with a suitable solvent, the content of the active agent can be analyzed by standard methods (HPLC, LC-MS). Release kinetics can be measured using standard release measuring apparatus. The ceramic approach can be combined with a polymeric (optionally biodegradable) coating approach.

Also, it is possible to similarly use various types of metal oxide coatings, eg iridium oxide as disclosed in US Patent 6245104B1. Accordingly, each reference below to alumina should be understood to also include other metal oxides, such as iridium oxide.

PTFE Membrane: Stent Graft

In this case a method similar to that described above is used. FK506 was deposited into the recesses of the porous PTFE membrane.

General Polymer Coating

Various polymers are suitable for loading active agents: methacrylate polymers, polyurethane coatings, PTFE coatings, hydrogel coatings. The active agent can be applied to the final surface (as described above) or it can be added directly to the polymerization solution. This technical method corresponds in other details to those already described above.

Various forms of polymers and combinations of the latter can be used, such as polymer mixtures, systems with layer structures, block copolymers and graft copolymers. Suitable polymers are acrylates and methacrylates, polysiloxanes such as polydimethylsiloxane, polymethylene malonate, polyethers, polyesters, bioabsorbable polymers, from vinyl Polymers of monomers such as polyvinylpyrrolidone and vinyl ether, poly-cis-1,4-butadiene, poly-cis-1,4-isoprene, poly-trans-1,4- Isoprene, and vulcanized products, polyurethanes, polyureas, polyamides, polyimides, polysulfonates, and biopolymers such as cellulose and its derivatives and proteins and fibrinsols . The hydrogel exhibits particularly interesting properties, since it appears to have a high water uptake and as the outermost layer (top coat) has very good hemocompatibility. Here it is possible to use hydrogels such as polyacrylamide, polyacrylic acid, polymers with oxygen as heteroatoms in the main chain, such as polyethylene oxide, polypropylene oxide, polytetrahydrofuran. Active agents can be applied to the final surface or entrapped in nanocapsules and/or liposomes for administration. However, the active agent can also be present directly in the polymerization solution or in the polymer solution. For some polymer/active agent systems, it is possible for the active agent to be immobilized by swelling.

mechanical method

The mechanical method is based on the formation of depressions in the stent holder by laser. These depressions can then be filled with FK506. Mechanical (depression) methods can be combined with an optionally biodegradable coating of the polymer, either itself loaded with an active agent. After the initial release from the polymer coating, the active agent can be released long term from the active agent filled recesses. This technical method corresponds in other details to those already described above.

A further preferred embodiment of the implant according to the invention is therefore that the implant has a ceramic coating, in particular an aluminum oxide coating, in which FK506 is incorporated.

Another preferred embodiment of the implant according to the invention is that the implant has a polymer coating, especially a methacrylate polymer, polyurethane, PTFE, hydrogel or hydrogel/poly Urethane blends, especially PTFE, have FK506 bonded thereto or have FK506 dissolved therein prior to forming the coating.

Another preferred embodiment of the implant according to the invention is that the metal of the implant has recesses introduced by laser, which are filled with FK506. It is particularly advantageous in this case that the metal provided with the recess filled with FK506 or at least that the recess be coated with a biodegradable polymer material, in which case FK506 is optionally bonded to the polymer coating, or FK506 Already dissolved into the polymer material prior to the polymerization of the coating.

In another advantageous embodiment of the implant according to the invention, the implant can be produced by the following method: wherein

a) use of implants with at least one closed or perforated layer or surface consisting of metal or metal alloys, homogeneous or formed of various thin bands, as claimed in claim 4, 6 or 7 As required by any one of 10 to 10, the implant is coated with a ceramic coating, in particular alumina; or

b) use of an implant having at least one closed or perforated layer or surface consisting of a polymer, homogeneous or formed by various thin bands, as claimed in any one of claims 5 to 10 as required; or

c) use of an implant as claimed in any one of claims 1 to 10, which is coated with a coating that has been polymerized or that polymerizes on the surface, especially methacrylate polymers, polyurethane, PTFE, water Gel or hydrogel/polyurethane blend coating; or

d) use of an implant as claimed in any one of claims 4, 6, or 7 to 10, having at least one closed or perforated layer or surface, the latter consisting of a metal or metal alloy, being homogeneous or formed from various thin strips, on which there are depressions formed by laser, the depressions are filled with FK506, and then the implant is coated with a biodegradable coating already polymerized or polymerized on the surface;

e) then contacting the implant according to a), b), c) or d) with a solution of FK506 in an aqueous or organic solvent, for example by spraying, misting or dipping (optionally under vacuum);

f) then, optionally drying the implant, preferably until the solvent of step e) is removed;

g) then, optionally repeating step e), optionally followed by step f), preferably several times, in particular 1 to 5 times; and

h) followed by optionally rinsing the implant one or more times with water or isotonic saline; and

i) Next step, optionally allowing it to dry.

In this context, preferably during the production of the implant according to the invention, the implant according to the invention can be produced in such a way that in step e) FK506 is dissolved in alcohol, preferably ethanol, in particular , FK506 is dissolved in ethanol at a concentration of 0.5-5 g/L and/or in step e), the implant is brought into contact with a solution of FK506 in an aqueous or organic solvent by immersion under vacuum, preferably overnight, and/or Either steps f) and/or g) are not performed and/or the implant is washed several times with saline in step h) and/or the implant is allowed to dry overnight in step i).

In another alternative preferred embodiment of the invention, preferably in the production of the implant of the invention which can be produced as described above, in step e) the implant is introduced preferably aseptically Into a preferably sterile container with a closure (closure) that can be perforated and can be closed after the perforation is completed, such as a vial for injection, FK506 is preferably aseptically introduced into the container. In the container, the latter is closed with a closure, wherein said closure can be perforated and closed after the perforation is completed, a thin, preferably sterile, gas-permeable ventilation tube (ventilation tube), such as a cannula, is perforated Through this closure, a vacuum is applied, then preferably the FK506 solution is agitated, and finally, preferably after about 12 hours, the thin, preferably sterile vent tube is removed and/or the FK506 is dissolved in alcohol, preferably in ethanol, specifically 3.3 mg of FK506 in 1 ml of ethanol, and/or retain the implant in a preferably sterile, closed glass container from step e), and/or step f) to i) are omitted.

In another advantageous embodiment of the implant of the present invention, the implant can be produced by the following method, wherein before forming at least one closed or porous layer or surface, FK506 has been dissolved in the polymeric reaction material, The layers or surfaces described therein consist of a polymer or a polymer coating of the implant.

It is particularly preferred that FK506 is released after implantation of the implant of the invention. Even more advantageous is delayed release. Here, a particularly preferred embodiment of the present invention is that, after implantation, FK506 is released from the implant for 24 hours, preferably 48 hours, more preferably more than 96 hours. Particularly advantageous: FK506

a) released in less than 48 hours, or

b) release from the implant for at least 48 hours, preferably at least 7 days, in particular at least 2 days up to 21 days after implantation; or

c) The implant shows both a) and b) release patterns.

The latter variant can in particular be obtained by using two different types of coatings, bonding or physical fixation. In one embodiment, the FK506-loaded laser pits are sealed with a FK506-loaded biodegradable film. A rapid release from the membrane was followed by a long-term release from the depression.

Another preferred embodiment of the present invention is that at least one other active agent, preferably a pharmaceutical active agent, is also present in the implant, in particular, another active agent is selected from the following active agents or derivatives thereof:

、硝苯地平、尼莫地平或其他Ca⁺⁺通道阻断剂、卡托普利、依那普利、赖诺普利、喹那普利或血管紧张素转化酶的其它抑制剂(血管紧张素转化酶抑制剂)、氯沙坦、candesartan、irbesartan、缬沙坦、或血管紧张素II受体的其它拮抗剂；(Group 1): morphine, lincidomine, sodium nitroprusside, nitroglycerin or general NO donors, stimulators of soluble guanylate cyclase (sGC), such as BAY41-2272 (5-(cyclo Propyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4-ylamine); hydralazine, vitamin lapamil, diltiazem

, nifedipine, nimodipine or other Ca ⁺⁺ channel blockers, captopril, enalapril, lisinopril, quinapril or other inhibitors of angiotensin converting enzyme (angiotensin converting enzyme inhibitors), losartan, candesartan, irbesartan, valsartan, or other antagonists of the angiotensin II receptor;

(Group 2): dexamethasone, betamethasone, prednisone or other corticosteroids, 17-beta-estradiol, cyclosporine, mycophenolic acid, VEGF, VEGF receptor activators, tranis Naproxen, meloxicam, celebrex, vioxx or other COX-2 antagonists, indomethacin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitors, plasminogen activators Inhibitor 1 (plasminogen activator inhibitor-1) or serine protease inhibitors (serpins); thrombin inhibitors such as hirudin, hirulog, agratroban, PPACK or interleukin-10;

(Group 3): Rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)rapamycin or other rapamycin derivatives, PDGF antagonists, paclitaxel or 7-hexanoyl - Taxol, cisplatin, vinblastine, mitoxantrone, combretastatin A4, topotecan, methotrexate, flavopiridol, actinomycin D, Rheopro/abciximab, or probucol .

More particularly preferred other active agents are selected from group 1 and are released from the implant within the first 24-72 hours after implantation, and/or if the other active agents are selected from group 2, within the first 48 hours to 21 days after implantation Release from the implant, and/or if the other active agent is selected from group 3, within a period of 14 days to 3 months after implantation.

The invention also relates to a method for producing the implant according to the invention, wherein FK506 has been dissolved in Polymerized materials.

The invention further relates to a method for producing an implant according to the invention, comprising the following steps:

a) The implant has at least one closed or perforated layer or surface of metal or metal alloy, homogeneous or formed by various thin bands, as claimed in any one of claims 4, 6, or 7 to 10 As required by subparagraph 1, the implant is coated with a ceramic coating, in particular with aluminum oxide; or

b) an implant with at least one closed or perforated layer or surface made of a polymer, homogeneous or formed by various thin bands, as claimed in any one of claims 5 to 10; or

c) The implant as claimed in any one of claims 1 to 10, which is coated with a coating already polymerized or polymerized on the surface, in particular methacrylate polymers, polyurethane, PTFE, Hydrogel or hydrogel/polyurethane hybrid coating; or

d) use of an implant as claimed in any one of claims 4, 6, 7 to 10, which has at least one closed or perforated layer or surface, the latter consisting of a metal or metal alloy, being homogeneous Or formed from various thin strips, on which there are depressions formed by laser, the depressions are filled with FK506, and then the implant is coated with a biodegradable coating material that has been polymerized or polymerized on the surface;

e) then contacting the implant according to a), b), c) or d) with a solution of FK506 in an aqueous or organic solvent, for example by spraying, misting or dipping (optionally under vacuum);

f) then, optionally drying the implant, preferably until the solvent of step e) is removed;

g) then, optionally repeating step e), optionally followed by step f), preferably several times, in particular 1 to 5 times; and

h) followed by optionally rinsing the implant one or more times with water or isotonic saline; and

i) Next step, optionally allowing it to dry.

This method is particularly preferred if, in step e), FK506 is dissolved in alcohol, preferably ethanol, in particular, FK506 is dissolved in ethanol at a concentration of 0.5-5 g/L and/or in step e) In e), the implant is brought into contact with a solution of FK506 in an aqueous or organic solvent by immersion under vacuum, preferably overnight, and/or steps f) and/or g) are not carried out, and/or steps h) Wash the implant several times with saline and/or allow the implant to dry overnight in step i).

In another preferred alternative of the method according to the invention, in step e), the implant is introduced, preferably aseptically, into a preferably sterile container with a perforable and closed after perforation. The closure of the sterile container, such as a vial for injection, FK506 is preferably aseptically introduced into the container, the latter is closed with a closure, wherein the closure can be perforated and closed after completion of the perforation, the A thin, preferably sterile, gas-permeable vent tube, such as a catheter, is pierced through the closure, vacuum is applied, the FK506 solution is then preferably agitated, and finally, preferably after about 12 hours, the thin, preferably sterile gas-permeable vent tube is Remove, and/or dissolve FK506 in alcohol, preferably ethanol, in particular 3.3 mg of FK506 in 1 ml of ethanol in step e), and/or leave the implant in a preferably sterile , in a closed glass container for use, and/or steps f) to i) are omitted.

This alternative method is particularly advantageous, which is not disclosed at all in the prior art, and is extremely advantageous in terms of costs and time as well as production steps, especially since the implants are available directly and already in sterile packaging. Of course, this is generally applicable and is not limited to FK506 but can be used for many active agents. However, this advantageous and simple approach has drawbacks, so this is a problem.

Accordingly, the present application further relates solely to a method of producing an implant coated with an active agent, generally described below, having the following steps:

a) introducing the implant preferably aseptically into a preferably sterile container, such as a vial for injection, which has a closure that is perforable and closed after completion of the perforation;

b) introducing into the container a preferably sterile solution of the active agent, preferably in an organic solvent with low vapor pressure, especially an alcohol such as ethanol or methanol;

c) closing the container with a closure which may be perforated and closed after the perforation has been completed;

d) perforating a thin, preferably sterile, gas-permeable ventilation tube, such as a cannula, through the closure;

e) optionally applying a vacuum and thereby preferably agitating the active agent solution;

f) Finally, after about 12 hours, preferably the thin, preferably sterile, gas-permeable ventilation tube is removed, and

g) optionally keeping the implant in the preferably sterile, closed glass container of step a) until use.

It is more advantageous for this general method that the implant of step a) has at least one metallic perforated or closed surface or layer, has a ceramic coating, has a polymer coating and/or has at least one polymer coating A porous, porous or closed surface or layer.

Likewise, preferred implants for this general method are stents, stent grafts, grafts, graft connectors, polymer surfaced stents, or catheters.

This general approach is more preferred if the active agent is selected from pharmaceutical active agents, such as immunosuppressants or antibiotics. Wherein said active agent is preferably selected from following active agents and derivatives thereof:

、硝苯地平、尼莫地平或其他Ca⁺⁺通道阻断剂、卡托普利、依那普利、赖诺普利、喹那普利或血管紧张素转化酶的其它抑制剂(血管紧张素转化酶抑制剂)、氯沙坦、candesartan、irbesartan、缬沙坦、或血管紧张素II受体拮抗剂；(Group 1): morphine, lincidomine, sodium nitroprusside, nitroglycerin or general NO donors, stimulators of soluble guanylate cyclase (sGC), such as BAY 41-2272 (5-( Cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4-ylamine); Hydralazine, verapamil, diltiazem

, nifedipine, nimodipine or other Ca ⁺⁺ channel blockers, captopril, enalapril, lisinopril, quinapril or other inhibitors of angiotensin converting enzyme (angiotensin converting enzyme inhibitors), losartan, candesartan, irbesartan, valsartan, or angiotensin II receptor antagonists;

(Group 2): dexamethasone, betamethasone, prednisone or other corticosteroids, 17-beta-estradiol, cyclosporine, mycophenolic acid, VEGF, VEGF receptor activators, tranis Naproxen, meloxicam, celebrex, vioxx or other COX-2 antagonists, indomethacin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitors, plasminogen activators Inhibitor 1 (plasminogen activator inhibitor-1) or a serine protease inhibitor; thrombin inhibitors such as hirudin, hirulog, agratroban, PPACK or interleukin-10;

(Group 3): sirolimus, rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)rapamycin or other rapamycin derivatives, PDGF antagonists, paclitaxel or 7- Caproyl-paclitaxel, cisplatin, vinblastine, mitoxantrone, combretastatin A4, topotecan, methotrexate, flavopiridol, actinomycin D, Rheopro/abciximab, or probucol;

Especially selected from:

(Group 1): morphine, lincidomine, sodium nitroprusside, nitroglycerin or general NO donors, stimulators of soluble guanylate cyclase (sGC), such as BAY 41-2272 (5-( Cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4-ylamine); Captopril , enalapril, lisinopril, quinapril, or other inhibitors of angiotensin-converting enzyme (ACE inhibitors), losartan, candesartan, irbesartan, valsartan, or angiotensin Other antagonists of hormone II receptors.

(Group 2): dexamethasone, betamethasone, prednisone or corticosteroids, FK506 (tacrolimus), VEGF, VEGF receptor activators, inhibitors of plasminogen activator 1 ( Plasminogen activator inhibitor-1) or a serine protease inhibitor;

(Group 3): sirolimus, rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)rapamycin or other rapamycin derivatives, PDGF antagonists, paclitaxel or 7- Caproyl-paclitaxel, mitoxantrone, combretastatin A4, flavopiridol.

The present invention further relates to the use of the implant according to the invention for the treatment or prevention of coronary or peripheral vascular constriction or occlusion, in particular constriction or stenosis or restenosis, preferably for the prevention of restenosis.

The present application further relates to the use of FK506 (hereinafter referred to as FK506) for coating or for the production of implants for the treatment or prevention of coronary or peripheral vascular constriction or occlusion, in particular constriction or stenosis or restenosis, preferably for the prevention of restenosis use.

If the implant is a stent, stent graft, graft, graft connector, guide wire, catheter or catheter pump, preferably a stent, stent graft, Grafts, graft connectors, in particular stents, stent grafts or polymer surfaced stents are then preferred for this use of FK506.

For the use of FK506, it is also preferred that the FK506 is bound or attached to the implant in such a way that it is released from the implant after implantation, preferably in a delayed manner.

The present invention also relates solely to the use of FK506 for the treatment or prevention of coronary or peripheral vascular constriction or occlusion, in particular constriction or restenosis, preferably for the prevention of restenosis. As mentioned above, FK506 has been found here to have particularly advantageous properties within the scope of the present application.

Within the scope of the present invention, stents, or grafts or stent grafts having or consisting of a polymer layer have proven to be particularly suitable for FK506. Implants of this type, collectively referred to within the scope of the present invention as polymer surface stents, have not previously been coated with an active agent. However, it has surprisingly been found that they are particularly suitable for the purposes of the present invention, as the studies carried out within the scope of the present application demonstrate, since they are easily loaded with active agents and transport them uniformly and effectively. However, this property is not limited to FK506, so the present application also relates solely to polymeric surface stents comprising at least one physiologically and/or Pharmaceutically active active agent. For the purposes of the present invention, a polymer surface stent means an endovascular implant having a polymer surface for the purposes of the present invention. In a broad sense, therefore, polymeric surface stents include polymer-coated or polymer-constructed grafts and stent grafts, graft connectors, stents. In a narrow sense, it refers to stents coated with or composed of polymers, and stent grafts.

For polymeric surface stents, it is preferred that the active agent is selected from pharmaceutically active agents such as immunosuppressants or antibiotics, preferably selected from the following active agents and their derivatives:

、硝苯地平、尼莫地平或其他Ca⁺⁺通道阻断剂、卡托普利、依那普利、赖诺普利、喹那普利或血管紧张素转化酶的其它抑制剂(血管紧张素转化酶抑制剂)、氯沙坦、candesartan、irbesartan、缬沙坦、或血管紧张素II受体的其它拮抗剂；(Group 1): morphine, lincidomine, sodium nitroprusside, nitroglycerin or general NO donors, stimulators of soluble guanylate cyclase (sGC), such as BAY41-2272 (5-(cyclo Propyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4-ylamine); hydralazine, vitamin lapamil, diltiazem

, nifedipine, nimodipine or other Ca ⁺⁺ channel blockers, captopril, enalapril, lisinopril, quinapril or other inhibitors of angiotensin converting enzyme (angiotensin converting enzyme inhibitors), losartan, candesartan, irbesartan, valsartan, or other antagonists of the angiotensin II receptor;

(Group 2): dexamethasone, betamethasone, prednisone or other corticosteroids, FK506 (tacrolimus), 17-β-estradiol, cyclosporine mycophenolic acid, VEGF, VEGF Receptor activators, tranilast, meloxicam, celebrex, vioxx or other COX-2 antagonists, indomethacin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitors, fibrin Inhibitor of lysinogen activator 1 (plasminogen activator inhibitor-1) or a serine protease inhibitor; thrombin inhibitors such as hirudin, hirulog, agratroban, PPACK or interleukin-10;

(Group 3): sirolimus, rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)rapamycin or other rapamycin derivatives, PDGF antagonists, paclitaxel or 7- Caproyl-paclitaxel, cisplatin, vinblastine, mitoxantrone, combretastatin A4, topotecan, methotrexate, flavopiridol, actinomycin D, Rheopro/abciximab, or probucol;

In particular selected from:

(Group 1): morphine, lincidomine, sodium nitroprusside, nitroglycerin or general NO donors, stimulators of soluble guanylate cyclase (sGC), such as BAY 41-2272 (5-( Cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-n]pyridin-3-yl]-pyrimidin-4-ylamine); Captopril , enalapril, lisinopril, quinapril, or other inhibitors of angiotensin-converting enzyme (ACE inhibitors), losartan, candesartan, irbesartan, valsartan, or angiotensin Other antagonists of hormone II receptors.

(Group 2): Inhibitors of dexamethasone, betamethasone, prednisone or other corticosteroids, FK506 (tacrolimus), VEGF, VEGF receptor activators, plasminogen activators1 (plasminogen activator inhibitor-1) or a serine protease inhibitor;

(Group 3): sirolimus, rapamycin, SDZ RAD (40-O-(2-hydroxyethyl)rapamycin or other rapamycin derivatives, PDGF antagonists, paclitaxel or 7- Caproyl-paclitaxel, mitoxantrone, combretastatin A4, flavopiridol.

and/or polymeric surface stents comprising at least two, preferably 2 or 3, physiologically and/or pharmaceutically active agents selected from one of groups 1 to 3, preferably a group of at most one active agent.

In a preferred embodiment of this polymeric surface stent, when the other active agent is selected from group 1 as described above, this active agent is released from the implant within the first 24-72 hours after implantation, And/or if the other active agent is selected from group 2 above, it is released from the implant within the first 48 hours to 21 days after implantation, and/or if the other active agent is selected from group 3 above, it releases from the implant within 14 hours after implantation Days to 3 months to release from the implant.

Generally applicable to the polymer surface stent according to the invention, all the above-described embodiments, production methods and uses of the implant comprising FK506 in particular are applicable to the polymer surface stent according to the invention Stents are also preferred, and the invention therefore also relates to these, as long as the embodiment is still a polymer surface stent.

The invention also relates to the treatment of a human or animal in need of such treatment with or by the implant or polymer surface stent of the invention.

The present invention is further illustrated by the examples in the following section, which should not be construed as limiting the invention.

Examples and drawings

Attached picture:

Figure 1 shows the release of FK506 from a coronary stent graft whose surface consisted of PTFE that had been loaded with FK506.

Figure 2 shows the release of candesartan and quinapril from a stent graft whose surface is composed of PTFE that has been loaded with candesartan and quinapril.

Figure 3 shows the release of candesartan and quinapril from a polyurethane coated stent to which the coating has been added candesartan and quinapril.

Figure 4 shows the release of candesartan and quinapril from a stent coated with a polyurethane/hydrogel blend to which candesartan and quinapril had been added.

Figure 5 shows the release of FK506 in the blood after corresponding coated stents were implanted in rabbits.

Figure 6 shows the intimal area on implanted stents with and without corresponding coatings containing FK506.

Figure 7 shows the inflammatory response to implantation of stents with and without corresponding coatings containing FK506.

Example

Example 1:

Loading of target compounds on stent grafts All values are expressed in micrograms.

Table 1

*Measured by AAS

A: Test performed with dissolved solids in which a stent graft with a PTFE polymer layer was dipped.

B: Test performed with an intravenous (i.v.) solution into which a stent graft with a PTFE polymer layer is dipped.

C: Test performed with an intravenous solution into which a polyurethane-coated stent was dipped.

Example 2

Release profiles of stent grafts of the present invention and polymer surface stents in general produced by various methods:

All values are expressed in micrograms.

To analyze the release of active agent, stents were incubated at 370C in 10 ml of PBS buffer (stabilized with sodium azide). After a defined time, 2 x 1 ml of the solution was withdrawn and analyzed. This 2 ml solution was replaced with fresh PBS buffer (stabilized with sodium azide).

The table below shows the total release of active agent in solution. This means that the amount of active agent in the withdrawn assay buffer is added to the next withdrawn amount.

Table 2

A: Test performed with dissolved solids in which a stent graft with a PTFE polymer layer was dipped.

table 3

FK506 (tacrolimus) 1 hour later 3 hours later 8 hours later 24 hours later 96 hours later 192 hours later Active Agent/Type A first stent 14 and 13 average 14 62 and 62 mean 62 92 and 99 mean 95 148 and 145 average 147 145 and 151 average 148 195 and 198 average 196 1 hour later 3 hours later 8 hours later 24 hours later 96 hours later A second stent 34 and 26 average 30 56 and 57 average 57 82 and 78 average 80 108 and 109 average 109 159 and 164 average 161 1 hour later 3 hours later 8 hours later 24 hours later 96 hours later A third stent 12 and 9 mean 11 47 and 43 average 45 101 and 93 average 95 154 and 155 average 154 184 and 190 average 187

A: Test performed with dissolved solids in which a stent graft with a PTFE polymer layer was dipped.

Table 4

C: Test performed with an intravenous solution into which a polyurethane-coated stent was dipped.

table 5

A: Test performed with dissolved solids in which a stent graft with a PTFE polymer layer was dipped.

Table 6

A: Test performed with dissolved solids in which a stent graft with a PTFE polymer layer was dipped.

Table 7

A: Test performed with dissolved solids in which a stent graft with a PTFE polymer layer was dipped.

Example 3

Production method of FK506 coated implant (1)

Dissolve 10 mg of FK506 in 3 ml of ethanol;

Immerse an uncoated stainless steel stent in this solution overnight under vacuum at room temperature;

●Wash three times with salt water, each time for 1 minute;

●Let dry overnight.

Example 4

Production method of FK506 coated stent graft (2)

●The amount of FK506 can be changed according to the length and diameter of the stent and according to the use in the body. Here, doses of 10-200 micrograms of FK506 per cm of stent length were used.

• Dissolve FK506 (appropriate for the desired dose) in ethanol in a small glass container and visually inspect the solution for crystals.

A non-pretreated stent graft ("JOSTENT CoronaryStent Graft") consisting of a sandwich of two layers of stainless steel stent and PTFE membrane was mounted on the stent Structural composition.

• Use a pipette to pipette an appropriate amount of FK506 solution (5 to 30 microliters) onto the mounted stent graft.

●This step can be repeated as needed to apply large amounts of FK506 to the implant, usually once or twice. Here, the procedure is repeated once.

• After the stent graft is fully loaded, it is carefully removed from the stent.

• After a brief drying (approximately 5 minutes) in air (with optional heat input), the stent is packaged.

• Inspect all stents under the lens and discard if medical floe is found.

Example 5

Production method of stent with ceramic coating coated with FK506 (3)

• Dissolve 50 mg of FK506 in 10 ml of ethanol in a glass container. Prepare all other concentrations of fluids from this stock solution by dilution (between 1:1 and 1:20) as required;

- Visually inspect the solution for crystals;

An unloaded stent coated with an aluminum oxide layer (as disclosed in PCT application WO 00/25841, see also Example 7 Ceramic coating) was mounted on the bracket;

• Add FK506 solution (5 to 50 microliters) dropwise onto the stent using a hypodermic syringe. This should distribute the solution over the entire stent;

● Carefully remove the loaded stent from the bracket;

• After a brief drying (approximately 5 minutes) in air (with optional heat input), the stent is packaged.

• Inspect all stents for medical floc under the lens and optionally discard.

Example 6

New alternative production method (4) (especially for FK506, but also for other active agents), especially for the production of sterile stents, stent grafts and/or polymeric surfaces Stent stent:

Use small injection vials not much larger than the stent used;

Aseptically place sterile coronary stents (CSGs) in sterile injection vials;

Add 0.5 mL of sterile-filtered FK506 solution (3.3 mg/mL in ethanol) to the vial;

●Close the vial with a rubber stopper;

pierce the middle of the rubber stopper with a sterile injection cannula with a sterile filter;

- place the vial horizontally on a tumbler unit under vacuum in a desiccator;

• Roll the vial under vacuum overnight;

●Remove the injection needle;

●No flushing;

●Sterile CSGs are ready for use.

Example 7

Selection of possible active agents for active agent-releasing stents, especially with multiple layers, such as polymer surface stents or stent grafts, etc.

The loading method is described as the technical method below.

The active agents listed also include derivatives and all types of salts, enantiomers, racemates, bases or free acids.

Of greatest interest here are stents, stent grafts and polymeric surface stents which contain and correspondingly release at least one, two or three of the following listed active agent.

The active agents listed are divided into groups 1-3 according to their preferred release profile or release time.

It is also preferred that the stents, stent grafts and polymeric surface stents comprise active agents from different groups.

Table 8

Phase I - Vasodilation (Group 1) Active agent released especially during the first 24-72 hours after implantation of the stent active agent Domine, lindromine, sodium nitroprusside, nitroglycerin or general NO donors; Stimulators of soluble guanylate cyclase, such as BAY 41-2272 (5-(cyclopropyl-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-n ]pyridin-3-yl]-pyrimidin-4-ylamine) Hydralazine Verapamil, diltiazem, nifedipine, nimodipine, or other Ca⁺⁺ channel blockers Captopril, enalapril, lisinopril, quinapril, or other inhibitors of angiotensin converting enzyme Losartan, candesartan, irbesartan, valsartan, or other angiotensin II receptor antagonists

Table 9

Phase II - Inhibition of Inflammation, Immunosuppression, Promotion of Endothelial Cell Growth, Inhibition of Cell Migration (Group 2) Active agents released especially during the first 2-21 days after implantation of the stent active agent Dexamethasone, betamethasone, prednisone, or other corticosteroids 17-β-estradiol FK506 (tacrolimus) Cyclosporine mycophenolic acid VEGF, VEGF receptor activator Tranilast Meloxicam, celebrex, vioxx, or other COX-2 antagonists Indomethacin, diclofenac, ibuprofen, naproxen, or other COX-1 inhibitors Plasminogen activator inhibitor-1 or other serine protease inhibitors Thrombin inhibitors such as hirudin, hirulog, agratroban, PPACK interleukin-10

Table 10

Phase III - Inhibition of Cellular Proliferation (Group 3) Active Agent Released Especially During the First 14 Days to 3 Months After Implantation of the Stent active agent Sirolimus, SDZ RAD (40-0-(2-hydroxyethyl)-rapamycin or other rapamycin derivatives PDGF antagonist Paclitaxel Cisplatin Vinblastine Mitoxantrone Combretastatin A4 Topotecan methotrexate flavopiridol

Localized administration of the active agent can be achieved by direct delivery from the active agent-loaded surface of a coronary or peripheral vascular stent. The active agent loaded surface of the stent can be obtained by using various technical methods. Each of these methods can be performed in such a way that the active agent is released from the surface either briefly (hours) or long-term (days). Release kinetics can be tuned by specific modifications of the surface, such as hydrophobic or hydrophilic side chains on polymeric supports or ceramic surfaces.

●Ceramic coating

The active agent (eg FK506 at 10 micrograms to 10 milligrams) can be loaded onto alumina coatings with porous surfaces by dipping, spraying or similar techniques (patent applications DE19855421, DE19910188, WO 00/25841). The dosage of the active agent is selected such that proliferation, migration and T cell responses are sufficiently inhibited while not affecting the healing process, depending on the type of target vessel and the condition of the patient. Active agents can be employed as aqueous or organic solutions, for example in DMSO, DMF and ethanol. After spraying or dipping (optionally under mild vacuum), the treated stent is dried and the procedure is repeated 1-50 times. After the final drying step, the stent can be rinsed with water or isotonic saline for 1 min at room temperature before drying. After the active agent has been dissolved with a suitable solvent, the content of the active agent can be analyzed by standard methods (HPLC, LC-MS). Release kinetics can be measured using standard release measurement equipment.

PTFE membrane: stent graft

A similar approach to that described above is used here. The active agent is deposited into the depressions of the porous PTFE membrane.

●General polymer coating

Many polymers are suitable for loading active agents:

Methacrylate polymer, polyurethane coating, PTFE coating, hydrogel coating. The active agent can be applied to the final surface (as described above) or it can be added directly to the polymerization solution. This technical method corresponds in other details to those already described above.

●Mechanical method

The mechanical method is based on indentations formed in the stent holder by cutting lasers. These depressions can then be filled with active agent. The mechanical (depression) method can be combined with a thin biodegradable coating itself loaded with active agent. After the initial release from the biodegradable coating, the active agent can be released long term from the active agent filled depressions. This technical method corresponds in other details to those already described above.

Example 8

Candesartan and Quinapril Release of Active Agents from (Polymer) Coated Implants:

a) Arranging a porous PTFE membrane on the stent. This membrane was then loaded with an active agent mixture of candesartan and quinapril (1 mg each). The two active agents are released simultaneously. Release was measured in PBS (phosphate buffered saline). Figure 2 shows the release of candesartan and quinapril from the active agents on the stent.

b) Applying a polyurethane coating to an open-cell stainless steel stent. An active agent mixture of candesartan and quinapril (15% each based on polyurethane content) was introduced into a 5% solution of polyurethane in dimethylacetamide and sprayed Apply it to the stent. Figure 3 shows the release of the corresponding active agent.

c) A polyurethane/hydrogel coating is applied to the open stainless steel stent. An active agent mixture of candesartan and quinapril (15% each based on polyurethane) was introduced into a 5% solution of the polymer blend in dimethylacetamide and sprayed by spraying. Apply it to the stent. Figure 4 shows the release of the corresponding active agent.

Example 9

Animal studies on the release kinetics and mode of action of FK506

A stainless steel coronary stent (JOSTENTFlex, 16 mm) was coated with an alumina ceramic layer. This coating was used as a support for FK506 (as described in Examples 5 and 7 under "Ceramic Coating"). Here, the stent was loaded with a total of 60 µg of FK506. In an animal study in rabbits (n=7), these FK506-coated stents and uncoated conventional stents were implanted into the carotid arteries of New Zealand rabbits. The release of FK506 and the effect of FK506 on the growth of intima and the formation of macrophages and lymphocytes were studied.

The release of FK506 was determined by measuring the amount of FK506 in blood of rabbits after 1 hour, 8 hours, 24 hours and 48 hours by HPLC. The excellent release kinetics of FK506 over time can be clearly seen in FIG. 5 . The rabbits were sacrificed after 28 days and the implanted stents were examined. The area of newly grown intima (neointima) within the stents was quantified under a light microscope. From Fig. 6, it can be clearly seen that the formation of neointima in the ceramic-coated stents loaded with FK506 was significantly reduced compared with the usual stents. There was a 53% reduction in the loading with 60 micrograms of FK506. And this decline was accompanied by a reduction in detectable inflammatory foci. As evident from Figure 7, the formation of macrophages and lymphocytes was also significantly reduced compared to the usual stents.

Thus, the use of a stent with a ceramic coating on which FK506 was applied resulted in a significant reduction in neointima and inflammatory foci after implantation.

Claims (48)

1. intracavity implant comprises FK506 and optional at least a other activating agent of the form of chemical covalent bond or non-covalent combination or physical fixation, and wherein said implant is designed to stent.

2. intracavity implant, the FK506 that comprises the form of chemical covalent bond or non-covalent combination or physical fixation, with optional at least a other activating agent, wherein said implant comprises the base material (substrate) that applies with FK506, and this base material has layer at least one sealing or perforation or surface, this layer or surface are made of metal or metal alloy, and be homogenizing or form by various faciolas.

3. as claim 1 or 2 each implants, it is characterized in that this implant is suitable for treatment or prevents crown or peripheral vessels constriction or obturation.

4. as the implant of claim 1 or 2, it is characterized in that this implant has layer at least one sealing or perforation or surface, this layer or surperficially constitute by polymer, and be homogenizing or form by various faciolas.

5. implant as claimed in claim 4, it is characterized in that at least one polymeric layer completely or partially cover constitute by metal or metal alloy, and be layer sealing homogenizing or that forms by various faciolas or perforation or surperficial.

6. implant as claimed in claim 4, it is characterized in that this implant has layer at least one sealing or perforation or surface, this layer or surface are made of metal or metal alloy, and be homogenizing or form by various faciolas, with layer at least one sealing or perforation or surface, this layer or surface are made of polymer, and be homogenizing or form by various faciolas.

7. implant as claimed in claim 6, it is characterized in that the layer or the surface that are made of metal or metal alloy are the optional cancellate structures that is made of metal or metal alloy, and/or be evenly sealing or that weave and/or be waterproof and/or not particulate thoroughly by layer or the surface that polymer constitutes, and/or the order on each layer and surface is metal-polymer from outside to inside, polymer-metal, metal-polymer-metal or polymer-metal-polymer, and/or, perhaps layer or the surface that is made of polymer non-chemically is connected to layer or the surface that is made of metal or metal alloy, and perhaps layer or the surface that is made of polymer is connected to layer or the surface that is made of metal or metal alloy by binding agent.

8. implant as claimed in claim 4 is characterized in that polymer is selected from: terylene, the foamable politef that maybe can not foam, polyurethanes, methacrylate polymers, hydrogel or hydrogel/polyurethane ester blend.

9. as the implant of claim 1 or 2, it is characterized in that implant is stent, stent graft, graft, graft connector, guide line, conduit or catheter pump.

10. as the implant of claim 1 or 2, it is characterized in that described implant applies with FK506.

11., it is characterized in that described implant has ceramic coating, is combined with FK506 above as the implant of claim 1 or 2.

12. implant as claim 11, it is characterized in that the coating that this ceramic coating completely or partially is aggregated thing covers, combine FK506 and/or other activating agents on optional this polymer coating or before applying this coating FK506 and/or other activating agent be dissolved in this coating.

13., it is characterized in that this implant has polymer coating as the implant of claim 1 or 2, be combined with FK506 above, perhaps FK506 is dissolved in wherein before applying this coating.

14. implant as claimed in claim 2 is characterized in that the metal of implant has the depression that forms by laser, the depression the inside is filled with FK506.

15. implant as claim 14, it is characterized in that disposing the metal of the depression of having filled FK506 or at least this depression apply with biodegradable polymeric, thereby, optional FK506 is attached on this polymer coating, and perhaps FK506 is dissolved in the polymeric material before applying this coating.

16., it is characterized in that FK506 exists with the nanoparticles of load or the form of liposome as the implant of claim 1 or 2.

17. as the implant of claim 1 or 2, it can produce by the following method, wherein:

A) use the base material with layer at least one sealing or perforation or surface, described layer or surface are made of metal or metal alloy, and be homogenizing or form by various faciolas, this base material applies with ceramic coating; Or

B) use the base material with layer at least one sealing or perforation or surface, described layer or surface are made of polymer, and be homogenizing or form by various faciolas; Or

C) use base material, it is with polymeric or carry out polymeric coating coating from the teeth outwards; Or

D) use base material, it has layer at least one sealing or perforation or surface, this layer or surface are made of metal or metal alloy, and be homogenizing or form by various faciolas, the depression that forms by laser is arranged in the above, in the depression filling FK506, then with polymeric or carry out polymeric biodegradable coating from the teeth outwards and apply this base material;

E) then will according to a), b), c) or d) base material and FK506 solution in aqueous or organic solvent, choose wantonly under vacuum, come in contact;

F) then, the base material of optionally drying through handling like this;

G) then, optional repeating step e), optional then step f); With

H) optional then water or isotonic saline solution clean base material one or repeatedly; With

I) optional its drying that then makes.

18. implant as claim 17, it is characterized in that in step e), FK506 being dissolved in the alcohol, and/or in step e), by under vacuum, flooding, implant is contacted with the solution of FK506 in aqueous or organic solvent, and/or execution in step f not) and/or g), and/or at step h) in salt water washing implant for several times and/or in step I) in make the implant dried overnight.

19. implant as claim 17, it is characterized in that in step e), implant is introduced in the container, this container has can be perforated and at the closure of finishing the perforation rear enclosed, FK506 is incorporated in this container, the latter seals with closure, wherein said closure can be perforated and finish the perforation rear enclosed, with thin, gas-pervious ventilation duct passes this closure, uses vacuum, and is last, thin air ventilation pipe is taken out, and/or FK506 is dissolved in the alcohol, and/or in step e), implant is retained in the glass container of sealing up to use, and/or step f) is to i) be omitted.

20. implant as claimed in claim 4, it can be by following method production, before the polymer coating that forms the layer that is made of polymer at least one sealing or perforation or surface or implant, FK506 has been dissolved in the polyreaction material in the method.

21., it is characterized in that implanting the back at implant discharges FK506 as the implant of claim 1 or 2.

22., it is characterized in that taking place to postpone to discharge as the implant of claim 21.

23., it is characterized in that FK506 discharges 24 hours from implant after implantation as the implant of claim 22.

24. the implant as claim 22 is characterized in that FK506

E) in less than 48 hours time, discharge, or

F) after implantation, discharge at least 48 hours from implant; Or

G) implant shows e) and f) two kinds of release profile.

25., it is characterized in that also comprising in the implant at least a other activating agent as the implant of claim 1 or 2.

26. as the implant of claim 25, wherein said other activating agent is selected from following activating agent or derivatives thereof:

Group 1: molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donor, the stimulus object of sGC; Hydralazine, verapamil, diltiazem

, nifedipine, nimodipine or other Ca ²⁺Other antagonist of other inhibitor, losartan, candesartan, irbesartan, valsartan or angiotensin-ii receptor of channel blocker, captopril, enalapril, lisinopril, quinapril or angiotensin converting enzyme;

Group 2: dexamethasone, betamethasone, prednisone or other corticosteroid medicines, 17-, cyclosporin, Mycophenolic Acid, VEGF, vegf receptor activator, tranilast, meloxicam, celebrex, vioxx or other COX-2 antagonisies, indomethacin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitor, plasminogen activator-1 or serpin; Thrombin inhibitor; IL-10 INTERLEUKIN-10;

Group 3: sirolimus, rapamycin, the SDZ RAD that is also referred to as 40-O-(2-ethoxy) rapamycin or other rapamycin derivatives, PDGF antagonist, paclitaxel or 7-hexanoyl-taxol, cisplatin, vinblastine, mitoxantrone, combretastatin A4, holder pool for may, methotrexate, flavopiridol, actinomycin D, Rheopro/ abciximab or probucol.

27. implant as claim 26, it is characterized in that if described other activating agent is selected from group 1, then this activating agent discharges from implant implanting in back 24-72 hour, if and/or described other activating agent is selected from group 2, then the latter discharges from implant in 48 hours-21 days in the implantation back, if and/or described other activating agent is selected from group 3, then the latter discharged from implant in back 14 days to 3 months time of implantation.

28. implant as claimed in claim 1, described implant are designed to the stent made by rustless steel.

29. a method that is used for producing as any one implant of claim 1 to 24 comprises the following steps:

Use

A) claim 2,5 or 6 to 9 each have that at least one is made of metal or metal alloy, homogenizing or form by various faciolas, the sealing or the perforation the layer or the surface implant, this implant applies with ceramic coating; Or

B) as each the layer or the implant on surface in the claim 4 to 9 with that at least one is made of polymer, homogenizing or that form by various faciolas, sealing or perforation; Or

C) each implant in the claim 1 to 9, it is with polymeric or carry out polymeric coating from the teeth outwards and apply, specifically the coating of methacrylate polymers, polyurethanes, politef, hydrogel or hydrogel/polyurethane ester blend; Or

D) as each implant in the claim 2,5 or 6 to 9, it has layer at least one sealing or perforation or surface, this layer or surface are made of metal or metal alloy, and be homogenizing or form by various faciolas, the depression that forms by laser is arranged in this layer or surface, in the depression filling FK506, then with polymeric or carry out polymeric coating from the teeth outwards and apply this implant;

E) then will according to a), b), c) or d) implant and FK506 solution in aqueous or organic solvent, choose wantonly under vacuum, come in contact;

F) then, this implant of optionally drying;

G) then, optional repeating step e), optional then step f); With

H) optional then water or isotonic saline solution flushing implant are one or more times; With

I) optional its drying that then makes.

30. method as claim 29, it is characterized in that in step e), FK506 being dissolved in the alcohol, and/or in step e), by under vacuum, flooding, implant is contacted with the solution of FK506 in aqueous or organic solvent, and/or execution in step f not) and/or g), and/or at step h) in salt water washing implant for several times and/or in step I) in make the implant dried overnight.

31. method as claim 29, it is characterized in that in step e), implant is introduced in the container, this container has can be perforated and at the closure of finishing the perforation rear enclosed, FK506 solution is incorporated in this container, the latter seals with closure, wherein said closure can be perforated and finish the perforation rear enclosed, with thin, gas-pervious ventilation duct passes this closure, uses vacuum, and is last, thin air ventilation pipe is taken out, and/or FK506 is dissolved in the alcohol, and/or in step e), implant is retained in the glass container of sealing up to use, and/or step f) is to i) be omitted.

32. be used for producing as each the method for implant of claim 4 to 9, wherein before the polymer coating that forms layer at least one sealing that is made of polymer or perforation or surface or implant, FK506 has been dissolved in the polyreaction material.

33. be used to produce the method for the intracavity implant that applies with the activating agent that comprises FK506 at least, it comprises the steps:

A) this implant is introduced container, this container has can be perforated and at the closure of finishing the perforation rear enclosed;

B) solution of activating agent is introduced this container;

C) with closure with this container closure, wherein said closure can be perforated and finish the perforation rear enclosed;

D) thin, gas-pervious ventilation duct are passed this closure;

E) the optional vacuum that applies;

F) last, with thin, gas-pervious ventilation duct takes out and

G) in the glass container of the optional sealing that this implant is retained in step a) till using.

34., it is characterized in that the implant of step a) has the surface or the layer of at least one metal, that bore a hole or sealing, has ceramic coating, has polymer coating and/or has surface or layer at least one polymer, perforation or that seal as the method for claim 33.

35., it is characterized in that implant is the stent or the conduit of stent, stent graft, graft, graft connector, polymer surfaces as the method for claim 33 or 34.

36., it is characterized in that activating agent is selected from pharmaceutically active agents as the method for claim 33.

37., it is characterized in that pharmaceutically active agents is immunosuppressant or antibiotic as the method for claim 36.

38., it is characterized in that pharmaceutically active agents is selected from following activating agent or derivatives thereof as the method for claim 36:

Group 1: molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donor, the stimulus object of sGC; Hydralazine, verapamil, diltiazem

, nifedipine, nimodipine or other Ca ²⁺Other antagonist of other inhibitor, losartan, candesartan, irbesartan, valsartan or the angiotensin-ii receptor of channel blocker, captopril, enalapril, lisinopril, quinapril or angiotensin converting enzyme;

Group 2: dexamethasone, betamethasone, prednisone or other corticosteroid medicines, 17-, cyclosporin, Mycophenolic Acid, VEGF, vegf receptor activator, tranilast, meloxicam, celebrex, vioxx or other COX-2 antagonisies, indomethacin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitor, plasminogen activator-1 or serpin; Thrombin inhibitor or IL-10 INTERLEUKIN-10;

Group 3: sirolimus, rapamycin, the SDZ RAD that is also referred to as 40-O-(2-ethoxy) rapamycin or other rapamycin derivatives, PDGF antagonist, paclitaxel or 7-hexanoyl-taxol, cisplatin, vinblastine, mitoxantrone, combretastatin A4, holder pool for may, methotrexate, flavopiridol, actinomycin D, Rheopro/ abciximab or probucol.

39. be used for the treatment of or prevent purposes in crown or peripheral vessels constriction or the inaccessible curable product in preparation as the implant of claim 1-28.

40.FK506 be used for applying or be used for production for treating or prevent crown or peripheral vessels constriction or the purposes of inaccessible implant.

41. the purposes of claim 40 is characterized in that this implant is stent, stent graft, graft, graft connector, guide line, conduit or catheter pump.

42. as the purposes of claim 40 or 41, it is characterized in that FK506 in such a way in conjunction with or be connected on the implant so that it is implanted the back at implant and discharges from implant.

43.FK506 be used for the treatment of or prevent purposes in crown or peripheral vessels constriction or the inaccessible medicine in preparation.

44. a polymer surfaces stent comprises the FK506 of form of chemical covalent bond or non-covalent combination or physical fixation and optional at least a other physiology and/or pharmaceutically active agents.

45., it is characterized in that described other activating agent is selected from pharmaceutically active agents as the polymer surfaces stent of claim 44.

46., it is characterized in that described pharmaceutically active agents is immunosuppressant or antibiotic as the polymer surfaces stent of claim 45.

47., it is characterized in that described pharmaceutically active agents is selected from following activating agent or derivatives thereof as the polymer surfaces stent of claim 45:

Group 1: molsidomine, linsidomine, sodium nitroprusside, nitroglycerin or general NO donor, the stimulus object of sGC; Hydralazine, verapamil, diltiazem

, nifedipine, nimodipine or other Ca ²⁺Other antagonist of other inhibitor, losartan, candesartan, irbesartan, valsartan or the angiotensin-ii receptor of channel blocker, captopril, enalapril, lisinopril, quinapril or angiotensin converting enzyme;

Group 2: dexamethasone, betamethasone, prednisone or corticosteroid medicine, 17-, cyclosporin, Mycophenolic Acid, VEGF, vegf receptor activator, tranilast, meloxicam, celebrex, vioxx or other COX-2 antagonisies, indomethacin, diclofenac, ibuprofen, naproxen or other COX-1 inhibitor, plasminogen activator-1 or serpin; Thrombin inhibitor or IL-10 INTERLEUKIN-10;

Group 3: sirolimus, rapamycin, the SDZ RAD that is also referred to as 40-O-(2-ethoxy) rapamycin or other rapamycin derivatives, PDGF antagonist, paclitaxel or 7-hexanoyl-taxol, cisplatin, vinblastine, mitoxantrone, combretastatin A4, holder pool for may, methotrexate, flavopiridol, actinomycin D, Rheopro/ abciximab or probucol.

48. polymer surfaces stent as claim 47, it is characterized in that if described other activating agent is selected from group 1, then this activating agent discharges from implant implanting in back 24-72 hour, if and/or described other activating agent is selected from group 2, then this activating agent discharges from implant in 48 hours-21 days in the implantation back, if and/or described other activating agent is selected from group 3, then this activating agent discharged from implant in back 14 days to 3 months time of implantation.

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